Pulsating transdermal drug delivery system

ABSTRACT

An electrophoretic/electro-osmotic transdermal drug delivery system for passing at least one drug, or therapeutic compound, through the skin membrane of a patient by way of a drug reservoir or gel for delivery to the systemic blood of a patient in selected, periodic pulsations. The system can be varied to accommodate various types of therapeutic compounds having varied characteristics and purposes. The system includes a current oscillator that applies periodic electrical variations to the system in order to trigger rhythmical variations of the potential and resistance of the skin membrane so as to cause oscillatory electro-osmotic streaming of the liquid with the therapeutic compound across the skin membrane in synchronization with the oscillator to the systemic blood of the patient in response to the rhythmical variations. The oscillator causes the power source to deliver a periodic pulsating current that alternates with periods of no current in the system or that alternates with periods of a different current. The pulsating current is of greater value than the; different current. The pulsating current is applied for relatively short periods relative the periods of non-current or the periods of different current. The different current can be either positive or negative current. During periods of negative current the liquid with the therapeutic compound can tend to be drawn from the skin membrane into the drug reservoir or gel.

RELATED U.S. PATENT APPLICATIONS

This is a continuation of application Ser. No. 598,803, filed Oct. 4,1990, and a continuation of Ser. No. 323,109, filed Mar. 13, 1989, nowabandoned, and a continuation of Ser. No. 055,518, filed May 28, 1987,now abandoned.

FIELD OF THE INVENTION

The present invention relates to transdermal drug delivery, or drugapplicator, systems and more particularly to electrophoretic transdermaldrug delivery systems including electro-osmotic and iontophoreticsystems that function by passing an electrical current through a drugpatch.

BACKGROUND OF THE INVENTION

Delivery of drugs to the systemic blood of a patient by means of anelectrophoretic/electro-osmotic transdermal system is generallyaccomplished primarily through the sweat and sebaceous ducts and theirrespective glands. Some delivery is made through the stratum cornum, orhorny layer. The stratum cornum, although very thin, is resistant to thepassage of both electrical current and of liquids. The skin ducts coveran area of about one-thousandth of the stratum cornum.

The drug delivery system of my patent application entitled "TransdermalDrug Delivery System" Ser. No. 028679, filed Mar. 20, 1987, describes asemi-dry drug patch and a selected current level delivered to thesemi-dry patch that combine to limit liquid containing a drug frommoving from the patch to the skin through the sweat and sebaceous ductsso as to starve the skin ducts of liquid and divert the current and theelectro-osmotic delivery of the drug through the stratum cornum. Areplenishment of the skin ducts with liquid occurs at periodic intervalsby an electro-osmotic delivery of the drug solution through the skinducts. An electrical oscillator can be added to the system so as toapply periodic current increases or pulsations in order to evacuate theskin ducts of water at intervals thus removing these electrical shuntsfrom the delivery system.

The skin of a human is of the type having skin ducts, type which iscommon to certain animals such as a horse, and so differs from the skinsof animals not having skin ducts, such as a rabbit. Nevertheless, thehuman skin also has characteristics taken in toto, not only separateduct and stratum cornum characteristics, and therefore can be consideredas a unitary cell membrane.

An article that discusses electro-osmotic processes of living membranesis "Electrokinetic Membrane Processes in Relation to Properties ofExcitable Tissues" by Torsten Teorell, published in Journal of GeneralPhysiology, 1959, Vol. 42, No. 4. A constant electrical current of afirst value was applied to a porous, charged membrane corresponding toan excitable cell membrane. The result was a repetitive oscillatoryprocess wherein the membrane at first periodically increased anddecreased in resistance over approximate half-hour time periods in whatthe author described as oscillations. The decreased level of cellmembrane resistance corresponded to oscillatory streaming of watersolution across the cell membrane. The repetitive oscillations dampenedafter about an hour and about three oscillations. When a constantelectrical current of a second value slightly greater than the firstcurrent value was applied to the same membrane, the repetitiveoscillations became undamped, that is, the oscillations continued atabout half-hour (in fact, slightly less) periods as long as the highercurrent continued to be applied. The "constant" electrical current infact naturally increased and decreased in response to lower and higherresistance states of the membrane.

Two different types of drugs, or therapeutic compounds, can be deliveredto the body. The therapeutic compound can be either a first type thatcorresponds to a naturally released body compound, such as a hormone asinsulin, or a second type that is foreign to the body, such asnitroglycerin, a cardiovascular drug, an oncological drug, and ananalgesic drug.

It is a phenomenon of many therapeutic compounds of the first type thatwhen they are delivered to the systemic blood of the patient in anoscillatory, or pulsating mode, two different effects will occurdepending upon the frequency of the drug delivery time relative to thenatural delivery rhythm of the body. If a therapeutic compound of thefirst type is delivered in periodic variations which are applied insimilar rhythms as the natural delivery rhythms of the body, theactivity of the naturally released body compound will be simulated. Ifsuch a therapeutic compound is delivered in periodic electricalvariations which are applied more often than the natural deliveryrhythms of the body, the natural activity of the body compound will beinhibited or extinguished.

It is also a phenomenon of many therapeutic compounds of the second typethat when they are delivered to the systemic blood of the patient in anoscillatory mode as compared to a steady state mode of delivery, adifferent effect on the patient occurs as compared to the steady statemode. The oscillatory mode is selected in accordance with bodyrequirements.

An example of a therapeutic compound of the first type that correspondsto a natural compound of the body is luteinising hormone-releasinghormone, or LHRH, which is also known as a gonadotrophin releasinghormone, or GnRH, and which controls production of testosterone in malesand inducement of ovulation in females. LHRH is released in accordancewith the natural rhythm of the body for approximately 6 minutes everyhour. A transdermal drug delivery system that delivers LHRH in a steadystate mode or at an increased frequency from the natural frequencyextinguishes gonadotrophic secretion: That is, the production of eithertestosterone in males or ovulation females ceases. On the other hand, atransdermal delivery system that delivers LHRH in a correct pulsatingmode in accordance with the natural rhythm of the body simulates, orensures, the mentioned processes. A natural compound of the body such asLHRH is released in accordance with a natural release rhythm of thebody. In the case of LHRH and many other natural compounds there existactive analogues that have certain advantages over the particularnatural compound. These active analogues are often used rather than thenatural compounds to trigger or to inhibit or extinguish body responses.

An example of a drug of the second type that is foreign to the body isnitroglycerin. It is known that the steady state delivery ofnitroglycerin to a heart patient via a transdermal drug delivery systemresults in a build-up of a tolerance to the drug by the body of thepatient in less than 24 hours so that the drug is rendered useless forthe 24-hour prophylaxis of stable angina pectoris. This matter isdiscussed in a paper entitled "Transdermal Nitroglycerin Patches inAngina Pectoris" by Udho Thadani et al., published in "Annals ofInternal Medicine" October 1986, Vol. 105, No. 4.

It is known that a pulsating electrical current can be applied to anelectrical circuit by various means, for example, by an oscillator inthe circuit. Pulsations of potential or current in a an electrophoreticdrug delivery system that are timed in accordance with an interplay ofdriving forces present in the drug delivery system including the skin asa transmembrane can accomplish timed drug deliveries that are moreprecise, reliable, and efficient than with delivery being made by thenatural undamped rhythmical variations of the transmembrane potentialand resistance caused by a selected steady state electrical currentapplied to the system. The term pulsation as used herein is a periodicincrease or decrease of a quantity, with the quantity herein havingreference to the quantity of either potential or current or amount of aliquid with a drug transported across the transdermal skin membrane.

In general, the present invention is applicable to drug delivery systemswhich involve drugs or therapeutic compounds whose delivery is dependentupon timing, quantity, and direction of current flow.

It is an object of this invention to provide anelectrophoretic/electro-osmotic transdermal drug delivery system thatrhythmically delivers a therapeutic compound, or drug, to the systemicblood of a patient in response to application of current pulsations tothe system which is otherwise devoid of current.

It is-another object of this invention to provide anelectrophoretic/electro-osmotic transdermal drug delivery system thatrhythmically delivers a therapeutic compound to the systemic blood of apatient by application of positive current pulsations with a negativecurrent being alternately applied to the system.

It is another object of this invention to provide anelectrophoretic/electro-osmotic transdermal drug delivery system thatrhythmically delivers a therapeutic compound to the systemic blood of apatient by application of negative current pulsations with a positivecurrent being alternately applied to the system.

It is another object of this invention to provide anelectrophoretic/electro-osmotic transdermal drug delivery system thatrhythmically delivers a therapeutic compound to the systemic blood of apatient by application of positive current pulsations with a differentpositive current being alternately applied to the system.

It is another object of this invention to provide anelectrophoretic/electro-osmotic transdermal drug delivery system thatrhythmically delivers a therapeutic compound to the systemic blood of apatient by application of negative current pulsations with a differentnegative current being alternately applied to the system.

It is another object of this invention to provide anelectrophoretic/electro-osmotic transdermal drug delivery system thatrhythmically delivers a therapeutic compound to the systemic blood of apatient by application of current pulsations so as to reinforce thenatural delivery rhythms of the body.

It is another object of this invention to provide anelectrophoretic/electro-osmotic transdermal drug delivery system thatrhythmically delivers a therapeutic compound to the systemic blood of apatient by application of current pulsations so as to inhibit or negatethe natural delivery rhythms of the body.

In accordance with these and other objects there is described herein anelectrophoretic/electro-osmotic transdermal drug delivery system forpassing at least one therapeutic compound through the skin membrane of apatient by way of a drug patch for delivery to the systemic blood of apatient in selected, periodic pulsations. The system can be varied toaccommodate various types of therapeutic compounds having variedcharacteristics and purposes. The system includes a current oscillatorthat applies periodic electrical variations to the system in order totrigger rhythmical variations of the potential and resistance of theskin membrane in synchronization with the oscillator so as to causeoscillatory electro-osmotic streaming of the liquid with the therapeuticcompound across the skin membrane to the systemic blood of the patientin response to the rhythmical variations. The oscillator causes thepower source to deliver a periodic pulsating current that alternateswith periods of no current in the system or that alternates with periodsof a different current than the pulsating current, The pulsating currentcan be applied for relatively short periods relative the periods ofnoncurrent or the periods of different current or can be applied forlong periods relative the periods of non-current of the periods ofdifferent current, The different current can be either positive ornegative current, During the periods of negative current the liquid withthe therapeutic compound tends to be drawn from the skin membrane intothe drug patch.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic representation of an electrophoretic drug deliverysystem having a drug patch in osmotic contact with the skin of a patientand including an oscillator that acts as a switch for the battery in thesystem;

FIG. 2 is a model graph that illustrates delivery of a therapeuticcompound to the skin of a patient by application of a pulsating currentto a system otherwise devoid of current in accordance with the systemshown in FIG. 1;

FIG. 3 is a model graph that illustrates delivery of a therapeuticcompound to the skin of a patient by both a positive current deliveryand positive pulsating current delivery in accordance with the systemshown in FIG. 1;

FIG. 4 is a schematic representation of an electrophoretic drug deliverysystem that supplies both a positive and a negative current to the drugpatch and that includes two batteries of opposite polarity in parallelin the system and a switch for reversing the current flow so as tosupply alternating positive and negative pulsations;

FIG. 5 is a schematic representation of an electrophoretic drug deliverysystem that supplies both a positive and a negative current to the drugpatch and that includes a polarity-reversing double-pole, double-throwswitch so as supply alternating positive and negative pulsations;

FIG. 6 is a model graph that illustrates delivery of a therapeuticcompound to the skin of a patient by alternating negative and positivepulsating current delivery;

FIG. 7 illustrates in isolated cross-section an integral cell membranethat includes a semipermeable membrane joined with the cover of the drugreservoir in adhesive and osmotic contact with the skin so as to form acell membrane integral with the skin; and

FIG. 8 is a model graph that illustrates flow of drug solution acrossthe skin in response to pulsating voltage application to the system.

DESCRIPTION OF THE PREFERRED EMBODIMENT

Reference is now made in detail to the drawings wherein the numeralsrefer to the same or similar elements throughout.

An electrical schematic diagram of an electrophoretic drug deliverysystem in accordance with the present invention shown in FIG. 1 includesa drug storage patch, shown for purposes of exposition as a reservoir12, and an electrode 14 each in contact with the skin, or cell membrane,16 of a patient. Reservoir 12 and electrode 14 are connected byconductors 18 and 20, respectively, to the positive and negativeterminals, or poles, of a battery 22. Reservoir 12 includes a liquidsuspension, or solution, 24 containing a therapeutic compound to bedelivered to the systemic blood of the patient. Solution 24 is containedby a cover 25 and a semipermeable adhesive gel 26 integral with cover 25and which is in contact with skin 16. The therapeutic compound to bedelivered to the patient is shown by way of example to be stored in themembrane-sealed drug reservoir described, but the therapeutic compoundcould be stored in a gel, or matrix, holding the therapeutic compound ina liquid suspension, or solution, throughout. A timer, or oscillator, 28is connected to the circuit. The timer or oscillator 28 causes currentreceived from battery 22 to be applied as current pulsations toreservoir 12 at selected periodic, or rhythmical, intervals so that theliquid in solution 24 along with the therapeutic compound is transportedfrom reservoir 12, which is in osmotic contact with skin 16, throughskin 16 to the systemic blood of the patient in undamped oscillatoryprocesses in response to the rhythmical applications of the current.

Oscillator 28 causes periodic electrical pulsations to be applied to thecircuit and particularly to reservoir 12 so as to trigger rhythmicalvariations of the potential and resistance of skin membrane 16 insynchronization with oscillator 28 so as to cause oscillatoryelectro-osmotic streaming of the liquid with the drug from reservoir 12across skin membrane 16 to the systemic blood of the patient in responseto the mentioned rhythmical variations of skin membrane 16.

FIG. 2 shows a model graph that illustrates a particular drug deliverysystem in accordance with the present invention and the schematicdiagram illustrated in FIG. 1. Current pulsations 30 are delivered toreservoir 12, and pulsating amounts of drug 32 are transported acrossskin 16 by oscillatory streaming to the systemic blood of the patient inresponse to the rhythmical variations of pulsations 30. Currentpulsations 30 are shown as being delivered at periodic one hourintervals for purposes of exposition, but the intervals could be betweena few minutes to a number of hours. Oscillatory amounts of drugdelivered increase gradually in response to pulsations 30, then over thenext hour gradually decrease in accordance with the depletion of thedrug in skin 16. A small amount of the drug is still retained in skin 16when the next current pulsation 30 is triggered by oscillator 28 andskin 16 again responds in an oscillatory process by transporting thedrug to the systemic blood of the patient. In this manner a predictablesupply of the drug is delivered to the patient in a predeterminedmanner. Delivery of drugs A, B, and C having long, medium, and shorthalf-lives 32A, 32B, and 32C, respectively, are illustrated. The time inthe ordinate axis is also a function of the transit time for theparticular drug. A long half-life drug A is delivered at a substantiallysteady state delivery mode that is highly advantageous over a deliveryby a steady state current in that the total amount of current deliveredis reduced with the result that electrochemical changes by the currentof drug A in the drug reservoir is reduced. A medium half-life drug B isillustrated with a substantial pulsating delivery to the systemic blood.A short half-life drug C, such as LHRH, has defined pulsations 32C. If,for example, electrical pulsations 30 were applied so as to cause drugpulsations 32C to last for 6 minutes every hour, this drug system wouldensure a natural supply of LHRH over an extended period of time with theresult that the production of testosterone in males or or induction ofovulation in females would be produced. If the system were designed todeliver electrical pulsations 30, for example, two or more times anhour, the gonadotrophic secretion would be extinguished in both malesand females. Such a system is useful in birth control and in treatmentof cancers. The start and finish of each drug delivery pulsationslightly lags the start and finish of each electrical pulsation.

In another embodiment of the invention, an electrophoretic drug deliverysystem in accordance with the schematic diagram shown in schematic inFIG. 1 is illustrated in a model graph in FIG. 3. Battery 22 ordinarilydelivers a positive current 38 and in response an amount of drug 40 isdelivered to the systemic blood of the patient. Oscillator 36 causescurrent value increases, or pulsations, 42, which are greater thancurrent 38, to be delivered to skin 16, which in response transports theliquid with the drug in undamped oscillatory streaming across skin 16 tothe systemic blood of the patient shown as oscillatory amounts of drugdelivered 44. Current pulsations 42 are shown as being delivered atperiodic one hour intervals for purposes of exposition, but the periodicintervals could be spaced between a few minutes to a number of hours.Amounts of drug delivered 44 increase gradually in response topulsations 42, then over the next hour gradually decreases towardsamount of drug delivered 40 in accordance with the depletion of liquidin skin 16. When the next current pulsation 42 is triggered byoscillator 36, skin 16 again responds in the oscillatory process byagain transporting the drug to the systemic blood of the patient. Inthis manner alternate amounts of drug 40 and pulsating amounts of drug44 are delivered to the systemic blood of the patient. Although only onedrug is shown, variations of the drug delivered in accordance with drugshaving long, medium, and short half-lives as shown in FIG. 2 can also beused in the system of FIG. 3.

The system shown in FIG. 3 is advantageous for the delivery of insulinto a patient. The body requirements of insulin are that it must becontinuously delivered to a patient, but extra quantities are requiredat certain times such as after meals. Oscillator 36 can be set to ortriggered to follow meals of the patient.

Another type of drug that can be used with the drug delivery systemshown in FIG. 3 is one of the anti-cancer drugs, which are mosteffective in the night hours when such a drug is less toxic to thepatient as it can be during daytime hours.

Another embodiment of the present invention is a drug delivery systemshown in an electrical schematic diagram in FIG. 4. A pair of batteries22A and 22B in parallel in the circuit are oriented in opposed polarrelationship with the circuit. A switch 48 connected to both batteries22A and 22B can be operated to alternately bring either battery 22A or22B into the circuit with the result that the direction of current flowin the circuit is alternatively reversed. A timer, or oscillator, 50causes switch 48 to be operated at periodic intervals. Battery 22Bgenerates a negative current at drug reservoir 12. Negative current atdrug reservoir 12 draws liquid with the drug present in skin membrane 16into solution 24 in drug reservoir 12. This action inhibits residues ofthe drug in skin membrane 16 from passing into the systemic blood of thepatient. At selected periodic intervals the timer activates oscillator50 to operate switch 48 so as to bring battery 22A into the circuit andisolate battery 22B from the circuit. The positive current that isgenerated by battery 22A is a much greater current than the low negativecurrent generated by battery 22B and in addition is applied for shortpulsation periods rather than the long pulsation periods of the negativecurrent. In response to the rhythmical applications of the positivecurrent, the liquid in solution 24 along with the drug is transportedfrom reservoir 12 into skin 16 to the systemic blood of the patient inoscillatory processes. At the end of each pulsation period, oscillator50 operates switch 48 to deactivate battery 22A and activate battery 22Bso as to create once again an alternate negative current at reservoir12.

FIG. 5 illustrates an alternate schematic diagram embodiment to thesystem shown in FIG. 4. A single battery 22C is connected to a solidstate, double-pole, double-throw switch 52 that can be activated by anoscillator 54 to reverse the direction of flow of current from positiveto negative and the reverse. Oscillator 54 causes a positive current toflow to drug reservoir 12 when switch 52 is activated in one currentflow direction, and causes a negative current to flow to drug reservoir12 when switch 52 is activated in the opposite current flow direction.

FIG. 6 shows a model graph that illustrates a drug delivery systemaccording to FIGS. 4 and 5. A negative current 56 is generated either bybattery 22B or by battery 22C so that a very low amount of drug 58 at alevel that is substantially zero is delivered to the systemic blood ofthe patient during the application of negative current 56. The reasonfor this phenomenon is that it is difficult to totally prevent drugmigration into the body of the patient once the drug is in skin membrane16. Positive current pulsations 60 are generated either by battery 22Aor by battery 22B so as to trigger rhythmical variations of thepotential and resistance of skin membrane 16 in synchronization withcurrent pulsations 60 so as to cause oscillatory electro-osmoticstreaming of the liquid with the drug across skin membrane 16 to thesystemic blood of the patient in amounts of drug delivered 62 inresponse to the mentioned rhythmical variations. Drugs having long,medium, and short half-lives analogous to drugs A, B, and C shown inFIG. 2 can be used in the system illustrated in FIG. 6.

An inverted image of the electrical current of the graph illustrated inFIG. 6 is possible as indicated by the reversed positive and negativesigns in parenthesis. The graph of FIG. 6 and the inverted image of thegraph relate to drugs that migrate from different poles.

FIG. 7 illustrates an integral excitable, or oscillatory, membrane 68that includes an adhesive gel semipermeable membrane 26A connected withcover 25 surrounding drug solution 24. Integral oscillatory membrane 26Ais in contact with skin 16 of a patient. An adhesive hydrogel interface70 is positioned between integral oscillatory membrane 26A and skin 16.Skin 16 is a part of integral oscillatory membrane 68. When integraloscillatory membrane 68 is positioned in the schematic systemsillustrated in FIGS. 1, 4, and 5, analogous results to the drug deliverysystems shown in the model graphs of FIGS. 2, 6, and 7 can be obtainedwith integral oscillatory membrane 68 acting as a unified oscillatorymembrane rather than skin 16 alone.

FIG. 8 is a model graph illustrating a pulsating voltage 72 applied tothe systems described in FIG. 1. A net flow, or flux, of the drugsolution is shown in movement across skin 16 or integral membrane 68. Apositive flux 74 results when voltage 72 is increased and a negativeflus 76 results when voltage 72 is decreased. The reason for thisphenomenon is the coupling between three driving forces of the pulsatingsystem, namely, gradients of drug concentration, membrane potential, andhydrostatic pressure within a charged membrane and in addition thepresence of a time delay of the resistance change of the membrane.

Although the present invention has been described in some detail by wayof illustration and example for purposes of clarity and understanding,it will, of course, be understood that various changes and modificationsmade in the form, details, and arrangements of the parts withoutdeparting from the scope of the invention as set forth in the followingclaims.

What is claimed is:
 1. An electrolytic transdermal patch for deliveringto the bloodstream of a patient different types of drugs comprising:(a)means defining a reservoir for containing a drug of said types of drugsand positioned in use in contact with the skin of the patient, (b) anelectrical source of power, (c) an electrical circuit having anelectrode positioned in use in contact with the skin of the patient andelectrically connecting the electrode, power source and said reservoir;and (d) means in said electrical circuit for causing periodic variationof current applied to said reservoir by said source of power in a pulsedmode in synchronization with a natural rhythmical variations of responseto a drug by the patient when said drug is foreign to the body of thepatient.
 2. The system of claim 1, wherein said means for effectingpulsation alternately applies a positive first current and a positivesecond current to said electrical circuit, said positive second currentbeing greater in value than said positive first current.
 3. The systemof claim 1 wherein said means for effecting pulsation alternatelyapplies a positive first current and a positive second current to saidelectrical circuit, said positive second current being such greater invalue than said positive first current.
 4. The system of claim 1 whereinsaid power source includes two batteries connected to said circuit; andsaid means for effecting pulsation includes a switch connected with saidcircuit capable either of connecting one battery of said two batterieswith said circuit in one polar orientation and simultaneouslydisconnecting the other battery of said two batteries from said circuitin the other polar direction and simultaneously disconnecting said onebattery from said circuit.
 5. The system of claim 4, wherein said meansfor effecting pulsation further includes an oscillator that alternatelyapplies an alternating negative first current and a positive secondcurrent to said circuit.
 6. The system of claim 4, wherein said meansfor effecting pulsation further includes an oscillator that alternatelyapplies a positive first current and a negative second current to saidcircuit.
 7. The system of claim 1, wherein said power source includes abattery connected to said circuit, and a solid state double-poled,double-throw switch connected to said battery, said double-throw switchbeing capable of reversing the polarity of said battery relative saidcircuit so as to reverse the direction of flow of current in saidcircuit.
 8. The system of claim 7 wherein said means for effectingpulsation further includes an oscillator that alternately applies annegative first current and a positive second current to said circuit. 9.The system of claim 7 wherein said means for effecting pulsation furtherincludes an oscillator that alternately applies a positive first currentand a negative second current to said circuit.
 10. The system of claim 1wherein said drug is a natural compound of the body or an activeanalogue thereof.
 11. The system of claim 1 wherein said drug is foreignto the body and said periodic variation of current are applied inaccordance with the body requirements of the particular drug.
 12. Anelectrolytic transdermal patch for delivering to the bloodstream of apatient different types of drug according to claim 1, in which saidmeans in said electrical circuit comprises means for effecting positivecurrent pulsations with a different positive current being alternatelyapplied to said reservoir.
 13. An electrolytic transdermal patch fordelivering to the bloodstream of a patient different types of drugsaccording to claim 1, in which said means in said electrical circuitcomprises means for effecting negative current pulsations with adifferent negative current alternatively applied to said reservoir. 14.An electrolytic transdermal patch for delivering to the bloodstream of apatient different types of drugs according to claim 1, in which saidmeans in said electrical circuit comprises an oscillator.
 15. Anelectrolytic transdermal patch for delivering to the bloodstream of apatient different types of drugs according to claim 14, in which saidoscillator causes the power source to deliver a periodic pulsatingcurrent that alternates with periods of no current in the system.
 16. Anelectrolytic transdermal patch for delivering to the bloodstream of apatient different types of drugs according to claim 1, in which saidmeans in said electrical circuit comprises a current oscillator foreffecting periodic electrical variations rhythmically to triggerrhythmical variations of the resistance of the skin in synchronizationwith said current oscillator to cause oscillatory electro-osmoticstreaming of a liquid therapeutic drug across the skin.
 17. Anelectrolytic transdermal patch for delivering to the bloodstream of apatient different types of drug according to claim 1, in which said insaid electrical circuit means comprises an oscillator for deliveringsaid drugs in which the delivery is dependent upon timing, quantity ordirection of current flow.